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Drug Interaction Report – Page 1 8th International Workshop on Clinical Pharmacology of HIV Therapy Drug Interaction Presentations at the
8th International Workshop on Clinical Pharmacology of HIV Therapy,
Budapest, April 2007.
This report summarises drug interaction studies presented at the recent meeting in Budapest. Abstracts, posters and presentations will be available at Existing Drugs . 2
New Drugs . 8
3TC- lamivudine, ABC- abacavir, APV-amprenavir, ATV-atazanavir, d4T-stavudine, ddI-didanosine, DRV-darunavir, Abbreviations: EFV-efavirenz, FPV-fosamprenavir, FTC-emtricitabine, IDV-indinavir, LPV-lopinavir, NFV-nelfinavir, NVP-nevirapine,
RTV-ritonavir, SQV-saquinavir, TDF-tenofovir Drug Interaction Report – Page 2 8th International Workshop on Clinical Pharmacology of HIV Therapy Abstract 22. Dose reduction of RTV in a once daily FPV/TDF/3TC regimen.
Steady-state pharmacokinetics of amprenavir, tenofovir, emtricitabine and ritonavir in HIV+ patients stabilized on fosamprenavir 1400 mg + FTC/TDF 200-300 mg once daily boosted by RTV 100 mg once daily (TELEX). Parks D, et al. The effect of reducing RTV from 200 to 100 mg once daily was studied in 12 HIV+ subjects receiving FPV/TDF/FTC (1400/200/300 mg once daily). Plasma concentrations of APV, TDF, FTC and RTV were determined prior to and 4 weeks after dose reduction of RTV. Median values for APV Cmin, Cmax and AUC were similar with both RTV doses (1708 vs 1911 ng/ml, 8303 vs 7601 ng/ml, 84260 vs 84910 ng.h/ml; RTV 200 vs 100 mg). Some changes were observed in TDF and FTC plasma pharmacokinetics but the impact on intracellular concentrations is not known. RTV Cmin and Cmax increased (80 vs 100 ng/ml, 1174 vs 1710 ng/ml) but AUC was unchanged (10230 vs 10250 ng.h/ml); the reason for this is unclear. Decreasing the RTV dose had no detrimental effects on pharmacokinetics and virological suppression was maintained and CD4 counts continued to rise. Abstract 25. Effect of food on ATV/RTV.
Effect of food on the pharmacokinetics of atazanavir when administered with ritonavir in healthy subjects. Child M, et al. ATV pharmacokinetics were determined in 39 HIV- subjects following administration of ATV/RTV (300/100 mg once daily) when fasted, or with a light meal (336 kcal, 14% fat), or with a high fat meal (951 kcal, 52% fat). When compared to PK parameters obtained when fasting, ATV Cmax increased 40% with a light meal and decreased 11% with a high fat meal; AUC increased 34% with a light meal and was unchanged with a high fat meal; Ctrough increased 40% with a light meal and increased 33% with a high fat meal. ATV absorption was delayed with a high fat meal with Tmax approximately doubling to 5 h. RTV AUC increased by 13% with a light meal and decreased by 10% with a high fat meal. ATV exposure when coadministered with RTV is optimised when dosed with food. Abstract 26. FPV with 100 or 200 mg RTV.
Assessment of amprenavir plasma levels in patients receiving once daily fosamprenavir in combination with either 100 or 200 mg ritonavir. Muret P, et al. A retrospective observational study looked at APV trough concentrations in HIV+ subjects receiving FPV (1400 mg once daily) with RTV (100 or 200 mg once daily). Median APV concentrations between the two groups were not statistically different (1340 vs 1520 ng/ml; 100 vs 200 mg RTV; n=25 vs n=24). 3TC- lamivudine, ABC- abacavir, APV-amprenavir, ATV-atazanavir, d4T-stavudine, ddI-didanosine, DRV-darunavir, Abbreviations: EFV-efavirenz, FPV-fosamprenavir, FTC-emtricitabine, IDV-indinavir, LPV-lopinavir, NFV-nelfinavir, NVP-nevirapine,
RTV-ritonavir, SQV-saquinavir, TDF-tenofovir Drug Interaction Report – Page 3 8th International Workshop on Clinical Pharmacology of HIV Therapy Abstract 32. Rifampicin and EFV.
The effect of rifampicin and cytochrome P450 2B6 genotype on efavirenz mid-dosing interval plasma concentrations in South African adults. Cohen K, et al. EFV concentrations (12-20 h post dose) were determined in South African subjects receiving EFV (600 mg once daily) and rifampicin (450 or 600 mg 5-times a week according to weight) in a study that also looked at CYP2B6 genotype. There was no significant difference (p=0.734) in median EFV concentrations between those taking rifampicin (n=40) and those taking EFV alone (n=102). Median EFV concentrations differed by CYP2B6 G516T genotype – GG 1600 ng/ml, GT 2100 ng/ml, TT 5900 ng/ml. This study provides evidence that EFV can be used with rifampicin in this population without dose adjustment. Abstract 41. LPV concentrations with Kaletra tablets and EFV.
Unpredictable lopinavir concentrations in HIV patients treated by lopinavir/ritonavir new
tablet formulation combined with efavirenz.
Barrail-Tran A, et al.
LPV concentrations were determined in 12 HIV+ subjects receiving Kaletra capsules
(533/133 mg twice daily n=7 or 400/100 mg twice daily n=5) coadministered with EFV prior
to and after switching to Kaletra tablets (400/100 mg twice daily n=9 or 600/150 mg n=3).
LPV trough concentrations were within the therapeutic range (3000-8000 ng/ml) in 11/12
subjects when receiving Kaletra tablets (one below target at 2410 ng/ml). Following the
switch to the tablet formulation, target concentrations were achieved in only 7/12 subjects
(one above target at 8500 ng/ml and four below target at 545, 2765, 2330 and 2035 ng/ml).
The larger interindividual variability observed in this study with the tablet formulation could
lead to subtherapeutic concentrations and suggests that TDM may be useful in optimising the
dose of Kaletra tablets.
LHPG Comment: Other larger studies have shown reduced variability with the tablet
formulation.
Abstract 50. Effect of PIs on RTV pharmacokinetics.
Differences between PI effects on plasma ritonavir levels: analysis of cross-over PK trials and clinical trials. Boffito M & Hill A. This literature-based analysis looked at the effect of PIs on RTV exposure with data being available from 16 cross-over PK studies (n=216). RTV AUC was increased by ATV (62%) and IDV (72%); SQV had no overall effect; levels were decreased by APV (43%), DRV (14%), NFV (51%), LPV (54%) and TPV (90%). The differential effects of PIs on RTV exposure may partly explain differences in lipid and adverse event profiles. Abstract 51. Unexpected adverse events with rifampicin and LPV.
Unexpected high incidence of nausea, vomiting and asymptomatic elevations of AST/ALT enzymes in healthy volunteers receiving rifampin and adjusted doses of lopinavir/ritonavir tablets. Nijland H, et al. A study looking at the interaction between rifampicin (600 mg once daily) and LPV/RTV (600/150 or 800/200 mg twice daily) in 11 HIV- subjects had to be terminated early due to 3TC- lamivudine, ABC- abacavir, APV-amprenavir, ATV-atazanavir, d4T-stavudine, ddI-didanosine, DRV-darunavir, Abbreviations: EFV-efavirenz, FPV-fosamprenavir, FTC-emtricitabine, IDV-indinavir, LPV-lopinavir, NFV-nelfinavir, NVP-nevirapine,
RTV-ritonavir, SQV-saquinavir, TDF-tenofovir Drug Interaction Report – Page 4 8th International Workshop on Clinical Pharmacology of HIV Therapy severe nausea, vomiting and elevated AST/ALT. No major complaints or laboratory abnormalities were noted during the first phase of the study (rifampicin alone), but 10/11 subjects suffered from nausea and/or vomiting following the addition of LPV/RTV. No LPV was detected in trough samples from 5/11 subjects (due to either no drug intake or vomiting); trough concentrations in 3 subjects receiving 600/150 mg were 6.7, 7.2 and 10.3 µg/ml and in 3 subjects receiving 800/200 mg were 8.3, 11.5 and 13.8 µg/ml. The reasons for the adverse events may be related to a) the sequence of drug administration, b) non-linear pharmacokinetics of LPV/RTV after intake of higher doses, or c) unknown factors which make healthy volunteers more susceptible to adverse events. Abstract 52. Effect of TPV/RTV on CYP450 enzymes using probe drugs.
Effects of tipranavir/ritonavir on the activity of cytochrome P450 enzymes 1A2, 2C9 and 2D6 in healthy volunteers. Vourvahais M, et al. The effect of TPV/RTV (500/200 mg once daily) on CYP 1A2, 2C9 and 2D6 was evaluated at first dose and steady state in 16 HIV- subjects receiving single doses of a cocktail of probe drugs containing caffeine (1A2), warfarin and vitamin K (2C9) and dextromethorphan (2D6). After the first dose, TPV/RTV slightly inhibited CYP1A2 and 2C9, and moderately inhibited CYP2D6. At steady state, slight induction of 2C9 was observed along with moderate induction of 1A2 and potent inhibition of CYP2D6. Concomitant administration of known CYP2D6 substrates should be used with caution with TPV/RTV. Abstract 54. Interaction between DRV/RTV and pravastatin.
Pharmacokinetic drug-drug interaction between the new HIV protease inhibitor darunavir
(TMC114) and the lipid-lowering agent pravastatin.
Sekar VJ, et al.
The effect of DRV/RTV (600/100 mg twice daily) on the pharmacokinetics of a single dose of
pravastatin (40 mg) was investigated in 14 HIV- subjects. Pravastatin Cmax and AUC
increased by 63% and 81% respectively. However, substantial interindividual variability in
pravastatin exposure was observed (treatment ratios from 0.57 to 6.79) and in 4/14 subjects,
pravastatin exposure was increased by over 200%. Coadministration was generally well
tolerated but, due to the variation in response, it is recommended to start with the lowest
possible dose of pravastatin and titrate as necessary whilst monitoring safety.
LHPG Comment: The mechanism of this interaction is intriguing and may involve the
hepatic influx transporter OATP1B1.
Abstract 56. Interactions between TDF and ABC, 3TC or LPV.
A pharmacokinetic study in HIV infected patients under tenofovir fumarate: investigation of systemic and intracellular interaction between TDF and abacavir, or lamivudine or lopinavir/ritonavir. Pruvost A, et al. The plasma and intracellular pharmacokinetic interaction between TDF and ABC, 3TC or LPV was investigated in HIV+ subjects receiving TDF + 3TC/LPV (n=7), TDF + 3TC/NVP (n=8), TDF + ABC/LPV (n=7) or TDF + ABC/NVP (n=5). Between group comparisons showed no significant interaction between TDF and ABC or 3TC. However, compared to values when given with NVP, ABC exposure when given with LPV was decreased (Cmax by 33%, AUC by 31%). In contrast, TDF exposure increased when given with LPV (39% 3TC- lamivudine, ABC- abacavir, APV-amprenavir, ATV-atazanavir, d4T-stavudine, ddI-didanosine, DRV-darunavir, Abbreviations: EFV-efavirenz, FPV-fosamprenavir, FTC-emtricitabine, IDV-indinavir, LPV-lopinavir, NFV-nelfinavir, NVP-nevirapine,
RTV-ritonavir, SQV-saquinavir, TDF-tenofovir Drug Interaction Report – Page 5 8th International Workshop on Clinical Pharmacology of HIV Therapy increase in Cmax, 72% increase in AUC) with intracellular tenofovir-DP AUC increasing by 35%. A gender effect was observed resulting in higher TDF-DP intracellular concentrations in females. Abstract 58. Tacrolimus pharmacokinetics when given with boosted PIs.
Effect of coadministered boosted protease inhibitors regimen on tacrolimus blood concentration in 3 kidney transplant HIV-infected patients. Barrail-Tran, A et al. Tacrolimus concentrations were monitored in three HIV+ patients following kidney transplantation. Antiretroviral regimens included LPV/RTV + EFV (Patient A), FPV/RTV (Patient B) and LPV/RTV (Patient C). Tacrolimus target concentrations were defined as 15-20 ng/ml immediately post transplant and then 8-12 ng/ml. Tacrolimus was initiated at doses of 0.5 mg for Patients A and B, and 1 mg for Patient C. Target concentrations were reached within 2 days for Patients A and B, and 12 h for Patient C. Patients A and B had to stop tacrolimus due to high concentrations (62 and 37 ng/ml, respectively). Tacrolimus half lives were calculated as 5.5 (A), 6.5 (B) and 8 (C) days. After reintroduction of reduced doses of tacrolimus, target concentrations were maintained with doses of 0.5 mg given every 2 days for Patient A, every 4 days for Patient B and every 8 days for Patient C. When given with boosted PIs, the initial dose of tacrolimus is critical, but unpredictable with reduced doses and daily TDM required. Abstract 59. Effect of omeprazole, food and formulation on TPV/RTV.
The effect of omeprazole, food and formulation on the pharmacokinetics of tipranavir coadministered with ritonavir. La Porte CJL, et al. The effect of omeprazole (40 mg once daily for 5 days) on a single dose of TPV/RTV (500/200 mg) given with food was studied in 15 HIV- subjects. No significant effect of omeprazole on TPV AUC and Cmax was observed. Another study looked at the pharmacokinetics of TPV/RTV (500/200 mg twice daily) in 32 HIV- subjects following administration of TPV capsules or oral solution, alone and with food. When given as the capsule formulation, the presence of food had no significant effect on the pharmacokinetics of TPV. When given as the oral solution, administration with food increased TPV Cmax by 21% with no change in AUC or Cmin. When both formulations were given with food, TPV exposure was higher with the oral solution (AUC 23%, Cmax 14%, Cmin 28%). Dose modification is not required with omeprazole and both formulations can be given with or without food. Abstract 60. Lack of interaction between omeprazole and LPV.
Acid reduction with a proton pump inhibitor does not affect pharmacokinetics of lopinavir or ritonavir in HIV-infected subjects in lopinavir/ritonavir-based therapy. Overton ET, et al. Pharmacokinetics of LPV were determined after administration of LPV/RTV (400/100 mg twice daily) alone and in combination with omeprazole (40 mg once daily) to 15 HIV+ subjects. No statistically significant effect of omeprazole on LPV exposure was observed (Cmax 9234 vs 11274 ng/ml; Cmin 4473 vs 5111 ng/ml; AUC 89.1 vs 98.5 mg.h/L; alone vs +omeprazole). Ritonavir pharmacokinetics were also unchanged in the presence of omeprazole. 3TC- lamivudine, ABC- abacavir, APV-amprenavir, ATV-atazanavir, d4T-stavudine, ddI-didanosine, DRV-darunavir, Abbreviations: EFV-efavirenz, FPV-fosamprenavir, FTC-emtricitabine, IDV-indinavir, LPV-lopinavir, NFV-nelfinavir, NVP-nevirapine,
RTV-ritonavir, SQV-saquinavir, TDF-tenofovir Drug Interaction Report – Page 6 8th International Workshop on Clinical Pharmacology of HIV Therapy
Abstract 61. Interaction between TPV/RTV and tadalafil.
The effect of tipranavir/ritonavir on the pharmacokinetics of tadalafil in healthy volunteers. Durant J, et al. The interaction between TPV/RTV (500/200 mg twice daily) and tadalafil (10 mg) was studied in 17 HIV- subjects after a single dose of TPV/RTV and at steady state. After the first dose of TPV/RTV, tadalafil AUC increased 133%, Cmax decreased 22% and Cmin increased 44%. At steady state, tadalafil AUC and Cmin were unaltered and Cmax decreased 30%. Tadalafil decreased TPV/RTV steady state exposure (TPV AUC 15%, Cmax 10%, Cmin 19%; RTV AUC 13%, Cmax 3%, Cmin 14%). If used within the first days of TPV/RTV treatment, tadalafil should be administered at the lowest possible dose. If TPV/RTV steady state has been achieved (after 7-10 days), no dose adjustment of tadalafil is needed. Abstract 62. Interaction between SQV/RTV and omeprazole in HIV+ subjects.
Saquinavir plasma pharmacokinetics during coadministration with omeprazole in HIV-infected subjects. Singh K, et al. The pharmacokinetics of SQV/RTV (1000/100 mg twice daily) were investigated in 12 HIV+ subjects administered omeprazole (40 mg once daily) simultaneously and 2 h apart. Omeprazole significantly increased saquinavir exposure when given simultaneously or 2 h apart. Saquinavir AUC, Cmin and Cmax increased by 54%, 73% and 55% when given simultaneously and increased by 67%, 97% and 65% when given 2 h apart. The mechanism of this interaction remains unclear. No significant changes were observed for saquinavir half life or ritonavir pharmacokinetics. Despite the significant increase in saquinavir exposure, no short term toxicities were noted. Abstract 64. LPV trough concentrations in the presence of ezetimibe.
The effect of ezetimibe on the steady-state trough levels of lopinavir/ritonavir. Klibanov OM, et al. Trough LPV concentrations were determined 13 HIV+ subjects stable on LPV/RTV and a statin prior to and 6 weeks after the introduction of ezetimibe. Concomitant use of ezetimibe did not affect LVP or RTV concentrations. Mean (± sd) trough concentrations of LPV alone and with ezetimibe were 5.7 ± 3.7 and 5.2 ± 4.4 µg/ml, respectively. RTV trough concentrations were 0.44 ± 0.56 and 0.37 ± 0.41 µg/ml, alone and with ezetimibe respectively. Abstract 66. Omeprazole interaction with ATV/RTV.
Effect of omeprazole 20 mg daily on the bioavailability of multiple-dose atazanavir with ritonavir in healthy subjects. Eley T, et al. This study in groups of HIV- subjects (n=14 per group) looked at the effect of a lower dose of omeprazole (20 mg) on the pharmacokinetics of ATV/RTV (300/100 or 400/100 mg once daily) when given with omeprazole either simultaneously or 12 h apart. When ATV was dosed in the evening, giving omeprazole 12 h apart, decreased ATV Cmax, AUC and Cmin by 39%, 42% and 46% respectively; giving omeprazole 12 h apart and increasing ATV to 400 mg resulted in decreases in ATV Cmax, AUC and Cmin of 29%, 28% and 24% respectively. When ATV was dosed in the morning ,giving omeprazole 1 h prior to ATV and increasing ATV to 400 mg decreased ATV Cmax, AUC and Cmin all by ~30%; giving omeprazole 12 h 3TC- lamivudine, ABC- abacavir, APV-amprenavir, ATV-atazanavir, d4T-stavudine, ddI-didanosine, DRV-darunavir, Abbreviations: EFV-efavirenz, FPV-fosamprenavir, FTC-emtricitabine, IDV-indinavir, LPV-lopinavir, NFV-nelfinavir, NVP-nevirapine,
RTV-ritonavir, SQV-saquinavir, TDF-tenofovir Drug Interaction Report – Page 7 8th International Workshop on Clinical Pharmacology of HIV Therapy apart and increasing ATV to 400 mg, resulted in decreases in ATV Cmax, AUC and Cmin of 20%, 29% and 37%. When compared to concentrations obtained with ATV 400 mg alone, all ATV/RTV + omeprazole combinations resulted in comparable ATV AUCs and ~2-fold increases in Cmin. Despite increasing ATV to 400 mg, when given with omeprazole ATV exposure was decreased by ~30% (relative to 300/100 mg alone) with the effect of omeprazole being similar when given either 1 h before or 12 h apart from ATV. Abstract 71. Effect of an NNRTI on LPV trough concentrations.
Analysis of plasma lopinavir levels when Kaletra (lopinavir /ritonavir 400/100 mg) tablets are administered with and without an NNRTI. Lechelt M, et al. LPV trough concentrations were determined in HIV+ subjects receiving Kaletra tablets twice daily alone (n=21) or with an NNRTI (n=26). Median trough concentrations were lower when administered with an NNRTI (6620 vs 5940 ng/ml, alone vs NNRTI). When specific dose combinations were studied, trough concentrations were 6620 ng/ml (400/100 alone, n=13), 5308 ng/ml (400/100 + NNRTI, n=8), 3400 ng/ml (600/150 alone, n=3), 9154 ng/ml (600/150 + NNRTI, n=7). Three patients receiving LPV/RTV once daily with an NNRTI all had trough LPV concentrations below the therapeutic range (1000 ng/ml). Abstract 72. Methadone pharmacokinetics in the presence of FPV/RTV.
Pharmacokinetics and pharmacodynamics of methadone enantiomers following coadministration with fosamprenavir and ritonavir in opioid-dependent subjects (col102577). Cao Y, et al. Pharmacokinetics of R- and S- methadone were determined in 19 HIV- subjects stable on methadone therapy prior to and after coadministration with FPV/RTV (700/100 mg twice daily). AUC and Cmax of active (R-) methadone decreased by 18% and 21% respectively in the presence of FPV/RTV; AUC and Cmax of inactive (S-) methadone decreased by 42% and 43%, respectively. Unbound R- methadone was unchanged and there was only a small decreased in unbound S- methadone (11% at 2 h, 19% at 6 h). Pharmacokinetics of APV were similar to historical controls. No subject required a change in methadone dose and there was no evidence of opiate withdrawal 14 days after the addition of FPV/RTV. 3TC- lamivudine, ABC- abacavir, APV-amprenavir, ATV-atazanavir, d4T-stavudine, ddI-didanosine, DRV-darunavir, Abbreviations: EFV-efavirenz, FPV-fosamprenavir, FTC-emtricitabine, IDV-indinavir, LPV-lopinavir, NFV-nelfinavir, NVP-nevirapine,
RTV-ritonavir, SQV-saquinavir, TDF-tenofovir Drug Interaction Report – Page 8 8th International Workshop on Clinical Pharmacology of HIV Therapy New Drugs
Abstract 53. Effect of different RTV doses on GS-9137.
Effect of increasing ritonavir doses on hepatic CYP3A activity and GS-9137 (elvitegravir) oral exposure. Mathias A, et al. The effect of different doses of RTV (20, 50, 100 or 200 mg once daily) on the pharmacokinetics of IV midazolam (1 mg) and oral GS-9137 (125 mg) was studied in 21 HIV- subjects. Midazolam systemic clearance was significantly reduced by all doses of RTV indicating substantial hepatic CYP3A induction. RTV doses of 50, 100 and 200 mg decreased apparent oral clearance of GS-9137 by 41%, 54% and 56% respectively (relative to 20 mg ritonavir). When compared to historical data for GS-9137 administered alone, 20 mg RTV produced a substantial increase in GS-9137 exposure. Dose response data indicate that RTV doses less than 100 mg are sufficient to boost oral GS-9137. Abstract 55. Effect of DRV/RTV on maraviroc.
An open, randomised, 2-way crossover study to investigate the effect of darunavir/ritonavir on the pharmacokinetics of maraviroc in healthy subjects. Abel S, et al. Coadministration of DRV/RTV (600/100 mg twice daily) and maraviroc (150 mg twice daily) was studied in 15 HIV- subjects. Maraviroc exposure increased in the presence of DRV/RTV (2.3-fold increase in Cmax, 4-fold increase in AUC). DRV and RTV pharmacokinetics were similar to historical data for DRV/RTV alone. A 50% dose reduction of maraviroc is recommended when coadministered with DRV/RTV. Abstract 57. Effect of TPV and RTV on vicriviroc.
The addition of tipranavir has no impact on the pharmacokinetics of vicriviroc when coadministered with a potent CYP3A4 inhibitor such as ritonavir. Sansone-Parsons A, et al . The pharmacokinetics of vicriviroc were determined in 8 HIV- subjects following administration of vicriviroc (15 mg once daily) with RTV (200 mg twice daily) or with TPV/RTV (500/200 mg twice daily). When compared to values obtained with RTV alone, vicriviroc pharmacokinetics were not significantly altered by the addition of TPV (Cmax 208 vs 184 ng/ml; AUC 3460 vs 3270 ng.h/ml; Cmin 117 vs 115 ng/ml; RTV vs TPV/RTV). RTV Cmax and AUC were both reduced by >50% after the addition of TPV. Dose modification of vicriviroc is not warranted when administered with TPV/RTV. Abstract 67. Effect of TMC278 on paracetamol (acetaminophen).
The effects of TMC278, a next generation non-nucleoside reverse transcriptase inhibitor, on the pharmacokinetics of acetaminophen and CYP2E1 activity in HIV-negative volunteers. Van Heeswijk R, et al. The interaction between TMC278 (150 mg once daily for 11 days) and paracetamol (500 mg single doses) was investigated in 16 HIV- subjects. There was no significant effect of TMC278 on paracetamol AUC or Cmax, nor on the AUCs of the glucuronide or sulphate metabolites. In another study in 16 HIV- subjects, no effect of TMC278 on CYP2E1 activity 3TC- lamivudine, ABC- abacavir, APV-amprenavir, ATV-atazanavir, d4T-stavudine, ddI-didanosine, DRV-darunavir, Abbreviations: EFV-efavirenz, FPV-fosamprenavir, FTC-emtricitabine, IDV-indinavir, LPV-lopinavir, NFV-nelfinavir, NVP-nevirapine,
RTV-ritonavir, SQV-saquinavir, TDF-tenofovir Drug Interaction Report – Page 9 8th International Workshop on Clinical Pharmacology of HIV Therapy was shown using chlorzoxazone as a probe substrate. No dose modification of TMC278 is needed if coadministered with paracetamol or chlorzoxazone. Abstract 68. Apricitabine pharmacokinetics in the presence of TPV/RTV.
Comparison of the pharmacokinetics of apricitabine in the presence and absence of ritonavir boosted tipranavir. Moore SM, et al. The pharmacokinetics of the new NRTI apricitabine (800 mg) were determined in 18 HIV- subjects when given alone and after 10 days of dosing with TPV/RTV (500/200 mg twice daily). Apricitabine Cmax and AUC increased by 25% and 40% in the presence of TPV/RTV. This increase is thought not to be of clinical concern and does not require any adjustment of dose. Abstract 69. Elvitegravir and acid reducing agents.
Pharmacokinetic evaluation of drug interactions with ritonavir-boosted HIV integrase
inhibitor GS-9137 (elvitegravir) and acid reducing agents.
Ramanathan S, et al.
The pharmacokinetics of GS-9137 (50 mg given with 100 mg RTV) were determined in
groups of HIV- subjects (~12 per group) when given alone, or after coadministration of
antacid (administered simultaneously or 2-4 h apart), or with omeprazole (40 mg).
Simultaneous coadministration with antacid decreased GS-9137 Cmax, AUC and Cmin by
47%, 45% and 41%, respectively. Separating the doses by 2 h decreased exposure by
10-20%, whereas separating the doses by 4 h resulted in similar exposure (<5% decrease) to
that obtained when given alone. Simultaneous coadministration with omeprazole did not alter
GS-9137 Cmax, AUC or Cmin. Omeprazole concentrations were consistent with historical
data. GS-9137, given with ritonavir, can be coadministered with omeprazole without dose
adjustment, but should be separated from antacid coadministration by at least 2 h.
LHPG Comment: The interaction with antacids is intriguing – a possible mechanism may be
binding to divalent cations.
Abstract 70. Elvitegravir and NRTIs
Lack of clinically relevant drug interactions between the ritonavir-boosted HIV integrase inhibitor GS-9137 (elvitegravir) and stavudine, didanosine or abacavir. Ramanathan S, et al. The effect of GS-9137 (200 mg given once daily with RTV 100 mg) on single doses of d4T (n=32), ddI (n=32) and ABC (n=24) were determined in HIV- subjects. There was no significant effect of GS-9137/RTV on the pharmacokinetics of d4T or ABC; ddI Cmax, AUC and Cmin decreased by 16%, 14% and 25%, respectively. GS-9137 exposure was not affected by single doses of d4T, ddI or ABC. No clinically relevant drug interactions were observed and no dose adjustments of GS-9137 are required when given with RTV and coadministered with d4T, ddI or ABC. 3TC- lamivudine, ABC- abacavir, APV-amprenavir, ATV-atazanavir, d4T-stavudine, ddI-didanosine, DRV-darunavir, Abbreviations: EFV-efavirenz, FPV-fosamprenavir, FTC-emtricitabine, IDV-indinavir, LPV-lopinavir, NFV-nelfinavir, NVP-nevirapine,
RTV-ritonavir, SQV-saquinavir, TDF-tenofovir

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